Although HIV-1 can induce strong antigen-specific T- and B-cells in almost all infected individuals, most of these adaptive immune responses are not protective against HIV-1 disease progression. Only in the very rare cases of elite controllers, effective T cell immune activity against HIV-1 is generated that can effectively block HIV-1 replication to undetectable levels. Similarly, B-cell responses that are able to broadly neutralize the majority of circulating viral species and effectively prevent HIV-1 transmission in animal models only emerge in a very small number of individuals. Yet, the mechanisms that support induction of such effective T- and B-cell immune responses in this small number of infected individuals, but not in the majority of alternative patients, are largely unclear. Dendritic cells (DCs) represent the most effective naturally-occurring antigen-presenting cells with critical roles for inducing antigen-specific T cell responses, and their decisive impact on the evolution of humoral immune responses is also increasingly being recognized. However, specific functional characteristics of DCs that are instrumental in generating protective HIV-1-specific T- and B- cell responses are unclear, despite the fact that almost all HIV-1 vaccine candidates rely on DCs for induction of adaptive immune responses. This application seeks to explore such mechanisms using a panel of novel, interdisciplinary methodological approaches. In specific aim 1, we propose to investigate the immunogenetic network between HLA class I molecules and Leukocyte Immunoglobulin-Like Receptors (LILR), a group of immunomodulatory MHC class I receptors expressed on DCs. We hypothesize that specific combinations of HLA class I and LILR allotypes result in improved functional activities of DCs, and their abilities to generate protective immune responses against HIV-1. In specific aim 2, we will explore cell-intrinsic immune responses against HIV-1 infection in DCs from elite controllers, and evaluate the influence of such innate immune activity on the function of ensuing HIV-1-specific T cell responses. These investigations are based on a large set of preliminary data demonstrating unique abilities of DCs from these patients to mount cell-intrinsic type I interferon responses against HIV-1, and may reveal a previously unrecognized network between innate and adaptive immune mechanisms in DCs that is critical for the induction of highly-protective HIV-1-specific T cell responses. In specific aim 3, we will explore functional properties of DCs in the small number of individuals who naturally develop broadly-neutralizing antibodies (bNAb)/neutralizing breadth (NB) against HIV-1, and investigate molecular signals in DCs that support bNAb/NB development through priming of specific populations of T follicular helper cell responses. By identifying specific functional aspects of DCs that are critical for the generation of effective immune responses against HIV-1 during natural infection, this work will contribute to the design of strategies to induce such immune responses in larger patient populations.